Background and purpose: Oxytocin is believed to be involved in ejaculation by increasing sperm number and contracting ejaculatory tissues. However, oxytocin may mediate these effects via oxytocin or vasopressin (AVP) receptors. The aim of this study was to determine the effect of oxytocin and AVP on peripheral tissues involved in ejaculation and to identify the receptor subtype(s) involved. Experimental approach: Standard tissue bath techniques were used to measure isometric tension from tissues involved in ejaculation and erection. Key results: Oxytocin and AVP failed to elicit a tonic contractile response in rat and rabbit testes, vas deferens, epididymis, seminal vesicles and prostate. In contrast, oxytocin and AVP elicited large tonic contractions in erectile (corpus spongiosum and corpus cavernosum) and ejaculatory (prostatic urethra, bladder neck and ejaculatory duct) tissues in a concentrationdependent manner. Conclusions and implications:The contractile effect of oxytocin on rat and rabbit ejaculatory and erectile tissues is mediated via V 1A receptors. Endothelin-1-induced contractions are not due to endogenous oxytocin or AVP release. V 1A receptor antagonists may have a therapeutic role in both erectile dysfunction and premature ejaculation.

Background and purpose: Hypothalamic neuropeptides centrally modulate sexual arousal. However, the role of neuropeptides in peripheral arousal has been ignored. Vascular and non-vascular smooth muscle relaxation in the vagina is important for female sexual arousal. To date, in vitro studies have focused on vaginal strips with no studies on vaginal arteries. The aim of this study was to compare the effects of sexual hypothalamic neuropeptides on rabbit vaginal wall strips and arteries. Experimental approach: Tissue bath and wire myography techniques were used to measure isometric tension from strips and arteries, respectively. Key results: Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) relaxed both preparations, effects that were only antagonized by the VIP/PACAP antagonist VIP6-28 (10 nM) and the PAC 1 antagonist PACAP 6-38 (1 mM). The melanocortin agonist a-melanocortin-stimulating hormone (1 mM), but not bremelanotide (1 mM), also relaxed both preparations.

Introduction Few treatments are available for men with premature ejaculation (PE); oxytocin (OT) receptor antagonism in the central nervous system (CNS) is a potential new approach. Aim To determine if cligosiban selectively inhibits human OT receptors, penetrates the CNS, shows pharmacology in the CNS, and effects ejaculatory physiology in pre-clinical systems. Methods Experiments complied with United Kingdom legislation and were subject to local ethical review. In vitro potency and selectivity of cligosiban was assessed using recombinant and native OT receptor systems including both neuronal and non-neuronal cell types. Selectivity was determined over neighboring V1A, V1B, and V2 vasopressin receptors using a combination of recombinant and native vasopressin receptor assay systems. To determine an effect on central OT receptors and on ejaculation, cligosiban was evaluated in 2 anesthetized rat models—the electromyography model of ejaculatory physiology and a model of OT-mediated CNS neuronal firing. The CNS penetration of cligosiban was also determined by measuring cerebrospinal fluid and plasma drug concentrations following an intravenous (IV) infusion in rats. Main Outcome Measure These were functional measures of pharmacology in vitro, in cell lines and tissues, and in vivo in rats. Results Cligosiban is a potent OT receptor antagonist, with a base dissociation constant of 5.7 nmol/L against native human uterine smooth muscle cell OT receptors. Cligosiban displays similar antagonistic potency against human recombinant and rat native OT receptors, including neuronal OT receptors. Cligosiban demonstrates >100-fold selectivity over human V1A, V1B, and V2 vasopressin receptors. In the electromyography model, cligosiban (0.9 mg/kg, IV bolus) reduced the bulbospongiosum burst pattern and contraction amplitude associated with ejaculation. In the anesthetized CNS neuronal firing model, the same dosing regimen of cligosiban (0.9 mg/kg IV bolus) modulated the OT-mediated response in the nucleus tractus solitarius. After systemic dosing to rats, cligosiban showed good CNS penetration. Clinical Implications As the first highly selective and centrally penetrant OT receptor antagonist, cligosiban represents a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. Strength & Limitations The pharmacology and selectivity of cligosiban is determined using functional assays in recombinant cell lines, native cell lines, and tissue. Functional outcomes in in vivo systems are linked to CNS measures of pharmacology. The translation of the animal models of ejaculation to PE in man is unproven. Conclusion Cligosiban, a potent, selective OT receptor antagonist, demonstrated CNS penetration and pharmacology and, using the same dosing regimen, inhibited apomorphine-induced ejaculation in rats. Cligosiban is a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE.